The proposed research involves the chemical synthesis and enzymological evaluation of certain nucleoside derivatives that are designed as transition state inhibitors of adenosine deaminase (ADA), the enzyme that is responsible for the in vivo degradation of a number of adenine nucleosides that are of interest in cancer chemotherapy. Within the past ca. four years these potent inhibitors of ADA, such as covidarabine (CoV, 2'-dexycoformycin), have been shown to potentiate the effects of nucleosides such as ara-A(9-Beta-D-arabinofuranosyladenine) toward certain neoplasms, especially those forms of leukemia that are resistant to the more traditional modes of therapy. Drug combination of certain adenine nucleosides (e.g. ara-A) with CoV have been suggested as possibly useful regimens for management of these leukemias in humans. Specifically it is proposed that certain lead compounds, such as CoV, will be used as model compounds on which to design analogs and explore structure-activity relationships for this new class of nucleosides, with the aim of establishing a clearer picture of the precise elements responsible for the potent inhibition exhibited by these inhibitors. In a practical sense, the possibility of synthesizing a simpler, more stable structure than the labile and expensive CoV, that would facilitate production and handling, is an attractive goal. Certain aspects of the medicinal chemistry of other less-potent inhibitors, (e.g. erthrohydroxynonyladenine, EHNA, and 9-(Beta-D-ribofuranosyl-l-6-dihydro-6-hydroxymethyl) purine) will also be studied. The chemical synthesis will be conducted alongside an in-house enzyme-assay program that will ensure maximum biological feedback to the chemist.